Inner ear disorders are an increasing problem in nowadays society. The most common of these disorders, tinnitus is commonly referred to as ‘ringing in the ears’—the perception of sounds in the absence of an external source of acoustic signals. Tinnitus has been defined as “the perception of a sound which results exclusively from the activity within the nervous system without any corresponding mechanical, vibratory activity within the cochlea, that is, tinnitus as an auditory phantom perception” (Jastreboff et al., J Am Acad Audiol 2000; 11(3): 162-177). For the individual patient, tinnitus may be tolerable or it may represent a debilitating illness preventing its sufferers from sleep or work. Tinnitus is frequently associated with a decreased sound tolerance (i.e. hyperacusis).
The pathophysiology of subjective tinnitus is poorly understood and a definitive pathogenesis of tinnitus is unknown. Many environmental and substance-induced factors may cause tinnitus. Among the most frequently cited factors are acute acoustic trauma, occupational noise, and recreational music. In general, tinnitus seems to be the result of neuronal dysfunction within the auditory pathway. This dysfunction is misleadingly perceived as sound by higher auditory centers and can lead to functional alterations within the auditory nervous system. Maladaptive functional changes in cortical structures could result in an altered balance between excitatory and inhibitory neurotransmission and may lead to more severe tinnitus. In all cases, a potential malfunction in auditory pathways and auditory cortex is related to the activity of the prefrontal cortex and limbic system.
In most cases (95%), the perceived tinnitus is purely subjective in nature, e.g. no physical source of acoustic signals can be identified and, therefore, cannot be heard externally. A physical examination is performed to exclude objective tinnitus, e.g. the patient's perception of sound is caused by a real source of sound waves, e.g. the sound from turbulent flow in blood vessels reaching the cochlea. Tinnitus may be classified according to duration of tinnitus and the degree of tinnitus expression (e.g. severity or annoyance of the tinnitus) (McCombe et al., Clin Otolaryngol 2001; 26(5): 388-393 and Davis et al., Epidemiology of Tinnitus. In: Tyler R, editor. Tinnitus Handbook. San Diego: Singular Publishing Group; 2000. p. 1-23). Regarding the impact of tinnitus, tinnitus may be severely annoying to the patient and can be accompanied by social and psychological complications.
There are currently no well-established, specific medical treatments for tinnitus that provide replicable reduction of tinnitus and annoyance due to tinnitus, in excess of placebo effects (Dobie, Laryngoscope 1999; 109(8): 1202-1211; Eggermont et al., Trends Neurosci 2004; 27(11): 676-682; and Patterson et al., Int Tinnitus J 2006; 12(2): 149-159).
1-Amino-alkylcyclohexanes such as neramexane (also known as 1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be useful in the therapy of various diseases especially in certain neurological diseases, including Alzheimer's disease and neuropathic pain. 1-Amino-alkylcyclohexanes such as neramexane are disclosed, for example, in detail in U.S. Pat. Nos. 6,034,134 and 6,071,966. Insofar as the chemical variations of 1-aminoaklylcyclohexanes are concerned, the respective subject matter of these patents is hereby incorporated by reference. It is believed that the therapeutic action of 1-amino-alkylcyclohexanes such as neramexane is related to the inhibition of the effects of excessive glutamate at the N-methyl-D-aspartate (NMDA) receptors of nerve cells, for which reason the compounds are also categorized as n NMDA antagonists, or NMDA receptor antagonists. Neramexane has also been disclosed to exhibit activity at the α 9/α 10 nicotinic (Plazas, et al., Eur J. Pharmacol., 2007 Jul. 2; 566(1-3):11-19) and 5-HT3 receptors).
Drug-related adverse events may be avoided or minimized by using a suitable up-titration period. Thus, a need exists for a suitable titration scheme which allows an effective dose to be quickly achieved while minimizing side effects. Moreover, a need also exists for a titration package which allows for compliance with a regimen of changing dosage of 1-amino-alkylcyclohexane derivatives over time. Such titration packages are also known as “compliance packages” as they aid the patient in complying with the therapeutically indicated dosage regime.
The present inventors have found that neramexane may be useful in treating tinnitus. The present inventors have also developed a titration scheme for the administration of a 1-amino-alkylcyclohexane derivative which allows for quick attainment of an effective dose of a composition comprising a 1-amino-alkylcyclohexane derivative while minimizing side effects. Moreover, the present inventors have developed a titration scheme allowing for a quick and safe up titration to at least two different and weight-adapted maintenance dosages. Moreover, the present inventors have developed a titration package comprising at least two different dosages of a 1-amino-alkylcyclohexane derivative, e.g. neramexane which allows for a suitable up-titration period to produce an acceptable number of occurrences of drug-related adverse events. Such a titration scheme/package may be suitable for use in the treatment of tinnitus.